title: Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I.
abstract: We report a family with autosomal-dominant hereditary systemic amyloidosis in three generations, presenting with renal involvement. Two members of the current generation received renal transplants for end-stage renal failure 16 and 18 years ago, and remain very well clinically despite massive visceral amyloidosis. Two other members of this generation, aged 32 and 47 years, have massive systemic amyloid but no clinical disability. Individuals known to be affected in previous generations died of renal failure in early adult life. Amyloid deposits in the proband, one of the transplanted individuals, were composed of apolipoprotein A-I (apoA-I), and among living family members there was complete concordance between amyloidosis and the presence of a novel 9 base pair in-frame deletion mutation in exon 4 of the apoA-I gene, causing a loss of residues Glu70Phe71Trp72. This predicts the acquisition of a single extra positive charge by mature apoA-I, and this variant was detected in the plasma of all carriers. All the previously reported amyloidogenic variants of apoA-I also carry an extra positive charge, indicating that this electrostatic change is likely to be relevant to the amyloidogenicity of apoA-I.
authors.affiliation: Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, England, United Kingdom.
authors.forename: M R
authors.initials: MR
authors.lastname: Persey
authors.forename: D R
authors.initials: DR
authors.lastname: Booth
authors.forename: S E
authors.initials: SE
authors.lastname: Booth
authors.forename: R
authors.initials: R
authors.lastname: van Zyl-Smit
authors.forename: B K
authors.initials: BK
authors.lastname: Adams
authors.forename: A B
authors.initials: AB
authors.lastname: Fattaar
authors.forename: G A
authors.initials: GA
authors.lastname: Tennent
authors.forename: P N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: M B
authors.initials: MB
authors.lastname: Pepys
mesh_terms: D000682:Amyloid / Q000032:analysis / Q000097:blood; D000686:Amyloidosis / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D016632:Apolipoprotein A-I / Q000032:analysis / Q000097:blood / Q000235:genetics*; D001706:Biopsy; D015153:Blotting, Western; D005091:Exons; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000097:blood / Q000235:genetics* / Q000601:surgery; D016030:Kidney Transplantation; D008099:Liver / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011877:Radionuclide Imaging; D017422:Sequence Analysis, DNA
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I